Simple Summary: Chronic lymphocytic leukemia (CLL) is a common leukemia characterized by an accumulation of lymphocytes in the blood and lymphoid organs. Disease presentation is highly variable as many patients do not initially require any treatment, and a watch and wait strategy remains the standard of care for up to 50% of patients. However, for those with a progressive disease, chemotherapy is the standard treatment and has improved over the years, increasing the survival of patients. We analyze here age-specific relative survival trends in CLL through 50 years up to 2020s in Denmark, Finland, Norway, and Sweden using the NORDCAN database. The large age-specific survival differences in 1972–76 almost disappeared by 2017–21. While 5-year survival in younger patients exceeded 90%, for those diagnosed at age 80–89-years, survival improved later, reaching 90% in Denmark and less in the other countries. Survival in Denmark is probably among the best in the world, which could be achieved by boosting survival even among the oldest patients. Most Nordic survival rates were better than those in the USA. Background: Chronic lymphocytic leukemia (CLL) is a common hematological malignancy with highly variable clinical presentation. Many patients never require any treatment but for the others, chemotherapy, immunochemotherapy, and newer targeted therapies have changed the treatment landscape. Diagnostic age influences the applied treatment, and we thus wanted to analyze age-specific survival trends through 50 years up to 2020s. Methods: We used 1- and 5-year relative survival from the NORDCAN database, with data from Denmark (DK), Finland (FI), Norway (NO), and Sweden (SE). Because of the variable presentation of CLL, we also considered incidence and mortality trends. For comparison, US SEER data were used. Results: The large age-specific survival differences in 1972–76 almost disappeared by 2017–21. While 5-year survival in younger patients exceeded 90%, for those diagnosed at age 80–89 years, survival reached 90% in DK and SE women, 80% in NO and SE men, but only 50% in FI. DK 5-year overall survival for men was 92.4%, and for women, it was 96.3%. These survival figures were higher than age-group-specific US survival data. Conclusions: The DK data are probably global top figures for national survival which could be achieved by boosting survival even among the oldest patients. The qualification to these figures and international comparisons is that survival needs to be considered in terms of incidence, which is high in DK and NO. Low survival of the FI 80–89-year-old patients, even in the first year after diagnosis, may suggest delayed diagnosis, which should call for a closer national scrutiny. [ABSTRACT FROM AUTHOR]
Background: The present study aimed to investigate physicians' perspectives on the diagnosis and treatment decisions for patients with non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mutations in a real-world setting in China using an online questionnaire. Methods: This study was performed via the CAPTRA-Lung collaboration between December 9, 2022 and March 6, 2023. The questionnaire was distributed digitally to physicians around China and was comprised of three sections: basic characteristics of surveyed physicians, diagnosis and treatment status of NSCLC patients with the EGFR exon20ins-mutation, and physicians' perspectives on treatment options. Physicians who treat more than 10 patients with advanced NSCLC every month and who have treated patients with advanced EGFR exon20ins-mutant NSCLC in the past six months were involved in this study. Results: A total of 53,729 questionnaires were distributed and 390 valid ones were collected. The EGFR mutation test was performed in 80.9% and 59.9% of patients receiving first-line or second-line therapy and beyond (hereinafter "second-line")therapy, respectively. In terms of treatment options, chemotherapy plus antiangiogenic therapy was the most common treatment option (30.0% of patients in first-line settings; 25.0% of patients in second-line settings), and a certain proportion of patients received novel EGFR exon20ins-targeted agents (including tyrosine kinase inhibitors [TKIs] and bispecific antibodies) in first- or second-line settings, which accounted for 11.9% and 15.7% of all treated patients, respectively. Additionally, physicians reported the highest satisfaction score for the efficacy and safety of targeted agents. Most physicians believed that EGFR exon20ins-targeted TKIs represented the most promising treatment option (80.2% in first-line treatment and 73.3% in second-line treatment). Among several novel agents under study, sunvozertinib has received the highest recognition for efficacy and safety. Conclusions: This study investigated the current diagnosis and treatment status and physicians' perspective, of patients with EGFR exon20ins-mutant NSCLC. The results highlight significant unmet clinical needs in this subgroup of patients. EGFR exon20ins-targeted TKIs were recognized as the most promising treatment regimen and may benefit more patients considering their awareness and acceptance of targeted therapy. [ABSTRACT FROM AUTHOR]
Huipeng Fang, Qiao Ke, Shiji Wu, Qiang Tu, and Lei Wang
Subjects
ADVERSE health care events, HEPATOCELLULAR carcinoma, OVERALL survival, TREATMENT effectiveness, PREVENTIVE medicine
Abstract
Background: Transarterial chemo(embolization) is preferred for treating unresectable hepatocellular carcinoma (uHCC); however, because of emerging immune-targeted therapies, its efficacy is at stake. This systematic review pioneers to evaluate the clinical efficacy and safety of transarterial chemo (embolization) combined with immune-targeted therapy for uHCC patients. Methods: PubMed, Embase, and Cochrane Library were searched for studies comparing immune-targeted therapy with or without transarterial chemo (embolization) until 31 May 2024. The complete response (CR) rate, objective response rate (ORR), and disease control rate (DCR) were considered to be the primary outcomes calculated for the clinical outcomes of transarterial chemo (embolization) combined with immune-targeted therapy, along with progressionfree survival (PFS) and overall survival (OS). The incidence of treatment-related severe adverse events was set as the major measure for the safety outcome. Results: Sixteen studies, encompassing 1,789 patients receiving transarterial chemo(embolization) plus immune-targeted therapy and 1,215 patients receiving immune-targeted therapy alone, were considered eligible. The combination of transarterial chemo(embolization) and immune-targeted therapy demonstrated enhanced outcomes in CR (OR = 2.12, 95% CI = 1.35-3.31), ORR (OR = 2.78, 95% CI = 2.15-3.61), DCR (OR = 2.46, 95% CI = 1.72-3.52), PFS (HR = 0.59, 95% CI = 0.50-0.70), and OS (HR = 0.51, 95% CI = 0.44-0.59), albeit accompanied by a surge in ALT (OR = 2.17, 95% CI = 1.28-3.68) and AST (OR = 2.28, 95% CI = 1.42-3.65). The advantages of additional transarterial chemo(embolization) to immune-targeted therapy were also verified in subgroups of first-line treatment, intervention techniques, with or without extrahepatic metastasis, Child-Pugh grade A or B, and with or without tumor thrombus. Conclusion: The combination of transarterial chemo(embolization) and immune-targeted therapy seems to bolster local control and long-term efficacy in uHCC, albeit at the expense of hepatic complications. [ABSTRACT FROM AUTHOR]
EGFR exon20ins, Real-world clinical practice, Targeted agents, Questionnaire, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract
Abstract Background The present study aimed to investigate physicians’ perspectives on the diagnosis and treatment decisions for patients with non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mutations in a real-world setting in China using an online questionnaire. Methods This study was performed via the CAPTRA-Lung collaboration between December 9, 2022 and March 6, 2023. The questionnaire was distributed digitally to physicians around China and was comprised of three sections: basic characteristics of surveyed physicians, diagnosis and treatment status of NSCLC patients with the EGFR exon20ins-mutation, and physicians’ perspectives on treatment options. Physicians who treat more than 10 patients with advanced NSCLC every month and who have treated patients with advanced EGFR exon20ins-mutant NSCLC in the past six months were involved in this study. Results A total of 53,729 questionnaires were distributed and 390 valid ones were collected. The EGFR mutation test was performed in 80.9% and 59.9% of patients receiving first-line or second-line therapy and beyond (hereinafter “second-line”)therapy, respectively. In terms of treatment options, chemotherapy plus antiangiogenic therapy was the most common treatment option (30.0% of patients in first-line settings; 25.0% of patients in second-line settings), and a certain proportion of patients received novel EGFR exon20ins-targeted agents (including tyrosine kinase inhibitors [TKIs] and bispecific antibodies) in first- or second-line settings, which accounted for 11.9% and 15.7% of all treated patients, respectively. Additionally, physicians reported the highest satisfaction score for the efficacy and safety of targeted agents. Most physicians believed that EGFR exon20ins-targeted TKIs represented the most promising treatment option (80.2% in first-line treatment and 73.3% in second-line treatment). Among several novel agents under study, sunvozertinib has received the highest recognition for efficacy and safety. Conclusions This study investigated the current diagnosis and treatment status and physicians’ perspective, of patients with EGFR exon20ins-mutant NSCLC. The results highlight significant unmet clinical needs in this subgroup of patients. EGFR exon20ins-targeted TKIs were recognized as the most promising treatment regimen and may benefit more patients considering their awareness and acceptance of targeted therapy.
Simple Summary: This review discusses the topic of prevention of brain metastases from the most frequent solid tumor types, i.e., lung cancer, breast cancer and melanoma. Within each tumor type, the issues of screening in asymptomatic patients, prophylactic strategies with radiation and secondary chemoprevention with targeted agents are discussed. This review discusses the topic of prevention of brain metastases from the most frequent solid tumor types, i.e., lung cancer, breast cancer and melanoma. Within each tumor type, the risk of brain metastasis is related to disease status and molecular subtype (i.e., EGFR-mutant non-small cell lung cancer, HER2-positive and triple-negative breast cancer, BRAF and NRAF-mutant melanoma). Prophylactic cranial irradiation is the standard of care in patients in small cell lung cancer responsive to chemotherapy but at the price of late neurocognitive decline. More recently, several molecular agents with the capability to target molecular alterations driving tumor growth have proven as effective in the prevention of secondary relapse into the brain in clinical trials. This is the case for EGFR-mutant or ALK-rearranged non-small cell lung cancer inhibitors, tucatinib and trastuzumab–deruxtecan for HER2-positive breast cancer and BRAF inhibitors for melanoma. The need for screening with an MRI in asymptomatic patients at risk of brain metastases is emphasized. [ABSTRACT FROM AUTHOR]
BackgroundTransarterial chemo(embolization) is preferred for treating unresectable hepatocellular carcinoma (uHCC); however, because of emerging immune-targeted therapies, its efficacy is at stake. This systematic review pioneers to evaluate the clinical efficacy and safety of transarterial chemo(embolization) combined with immune-targeted therapy for uHCC patients.MethodsPubMed, Embase, and Cochrane Library were searched for studies comparing immune-targeted therapy with or without transarterial chemo(embolization) until 31 May 2024. The complete response (CR) rate, objective response rate (ORR), and disease control rate (DCR) were considered to be the primary outcomes calculated for the clinical outcomes of transarterial chemo(embolization) combined with immune-targeted therapy, along with progression-free survival (PFS) and overall survival (OS). The incidence of treatment-related severe adverse events was set as the major measure for the safety outcome.ResultsSixteen studies, encompassing 1,789 patients receiving transarterial chemo(embolization) plus immune-targeted therapy and 1,215 patients receiving immune-targeted therapy alone, were considered eligible. The combination of transarterial chemo(embolization) and immune-targeted therapy demonstrated enhanced outcomes in CR (OR = 2.12, 95% CI = 1.35–3.31), ORR (OR = 2.78, 95% CI = 2.15–3.61), DCR (OR = 2.46, 95% CI = 1.72–3.52), PFS (HR = 0.59, 95% CI = 0.50–0.70), and OS (HR = 0.51, 95% CI = 0.44–0.59), albeit accompanied by a surge in ALT (OR = 2.17, 95% CI = 1.28–3.68) and AST (OR = 2.28, 95% CI = 1.42–3.65). The advantages of additional transarterial chemo(embolization) to immune-targeted therapy were also verified in subgroups of first-line treatment, intervention techniques, with or without extrahepatic metastasis, Child–Pugh grade A or B, and with or without tumor thrombus.ConclusionThe combination of transarterial chemo(embolization) and immune-targeted therapy seems to bolster local control and long-term efficacy in uHCC, albeit at the expense of hepatic complications.Systematic review registrationhttp://www.crd.york.ac.uk/PROSPERO/, identifier 474669.
Su, Yi-Chia, Wu, Chih-Chien, Chen, Yu-Hsun, Su, Chien-Chou, Chang, Yu-Ching, Hsieh, Meng-Che, and Kao Yang, Yea-Huei
Abstract
Background: Primary tumor resection and metastasectomy may be beneficial for many patients with metastatic colorectal cancer (mCRC). Objective: To assess the differences in postoperative survival outcomes between adjuvant therapy with chemotherapy alone and chemotherapy plus targeted agents (TAs). Design: Retrospective cohort study. Methods: Patients with mCRC who underwent surgical resection for primary colorectal tumor and distant metastases and received adjuvant therapy from 1 January 2010 to 31 December 2017 were enrolled in the Taiwan Cancer Registry. We analyzed the overall survival of patients with resectable or initially unresectable mCRC who received adjuvant chemotherapy alone and chemotherapy plus TAs. Results: We enrolled 1124 and 542 patients with resectable and initially unresectable mCRC, respectively. Adjuvant chemotherapy plus TAs and chemotherapy alone resulted in similar mortality rates among patients with resectable mCRC [adjusted hazard ratio (aHR) = 1.13; 95% confidence interval (CI), 0.93–1.36]; however, it marginally reduced the mortality rate among patients with initially unresectable mCRC who underwent conversion surgery after neoadjuvant therapy (aHR = 0.81; 95% CI, 0.62–1.06). The subgroup analysis of patients who received more than nine cycles of TAs preoperatively and anti-epidermal growth factor receptor agents revealed aHRs of 0.48 (95% CI, 0.27–0.87) and 0.33 (95% CI, 0.18–0.60), respectively. Conclusion: Adjuvant chemotherapy plus TAs may improve survival in patients with initially unresectable tumors who underwent conversion surgery following neoadjuvant therapy with TAs, especially in those who respond well to the targeted therapy. Our study underscores the importance of stratifying patients with mCRC based on tumor resectability when selecting the adjuvant therapy regimen. [ABSTRACT FROM AUTHOR]
Simple Summary: In a comprehensive analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and the CLL13 trials, we assessed the impact of first-line treatments with targeted agents (TAs), or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT), on overall survival (OS) compared to age- and sex-matched individuals in the general population. TAs demonstrated a higher 5-year restricted mean survival time (RMST) (58.1 months; 95% CI: 57.4 to 58.8) compared to CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Moreover, the comparison with age- and gender-matched general populations (AGMGP) suggested that TAs may mitigate CLL's impact on OS during the first five years post-treatment initiation. In contrast, CLL patients treated with FCR exhibited sustained OS differences compared to both the Italian and US AGMGP cohorts. These results support TAs as the preferred first-line treatment for younger/fit CLL patients but imply the need for a careful interpretation due to variations in patient selection criteria and clinical profiles across trials. Longer follow-up is essential to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. To assess the impact of first-line treatment with targeted agents (TAs) or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT) on overall survival (OS) compared to age- and sex-matched individuals in the general population, we conducted an aggregated analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and CLL13 trials. The restricted mean survival time (RMST), an alternative measure in outcome analyses capturing OS changes over the entire history of the disease, was used to minimize biases associated with the short follow-up time of trials. Patients treated with TAs demonstrated a higher 5-year RMST (58.1 months; 95% CI: 57.4 to 58.8) compared to those treated with CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Furthermore, the OS comparison of treatment groups with the AGMGP suggests that TAs may mitigate the impact of CLL on OS during the first five years post-treatment initiation. In summary, the 5-year RMST difference was −0.4 months (95% CI: −0.8 to 0.2; p = 0.10) when comparing CLL patients treated with TAs to the Italian age- and gender-matched general population (AGMGP). A similar trend was observed when CLL patients treated with TAs were compared to the US AGMGP (5-year RMST difference, 0.3 months; 95% CI: −0.1 to 0.9; p = 0.12). In contrast, CLL patients treated with FCR exhibited sustained OS differences when compared to both the Italian cohort (5-year RMST difference: −1.6 months; 95% CI: −2.4 to −0.9; p < 0.0001) and the US AGMGP cohort (5-year RMST difference: −0.9 months; 95% CI: −1.7 to −0.2; p = 0.015). Although these results support TAs as the preferred first-line treatment for younger CLL patients, it is crucial to acknowledge that variations in patient selection criteria and clinical profiles across clinical trials necessitate a cautious interpretation of these findings that should be viewed as directional and hypothesis-generating. A longer follow-up is needed to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. [ABSTRACT FROM AUTHOR]
Simple Summary: Advancements in treating patients with metastatic colorectal cancer have shown remarkable progress in the last two decades. Enhanced comprehension of tumor biology via molecular profiling has broadened treatment avenues. The approach to treating patients with metastatic colorectal cancer has evolved from a uniform method to a more individualized one. It's now clear that colorectal cancer manifests in diverse forms, characterized by varied molecular subtypes and genetic mutations, demanding personalized treatment approaches. This review delves into the latest clinical findings concerning late-stage treatment options for patients with metastatic colorectal cancer, mainly focusing on randomized trials wherever available. We include recommendations for options in unselected patients and therapies that should only be offered in patients with distinct tumor profiles. Systemic treatment of metastatic colorectal cancer (mCRC) has improved considerably over the past 20 years. First- and second-line combinations of 5FU, oxaliplatin, and irinotecan, with or without anti-angiogenic and/or anti-EGFR antibodies, were approved shortly after the turn of the millennium. Further triumphs were not seen for almost 10 years, until the approval of initially regorafenib and shortly after trifluridine/tipiracil. A growing understanding of tumor biology through molecular profiling has led to further treatment options. Here, we review the most recent clinical data for late-line treatment options in mCRC, focusing on randomized trials if available. We include recommendations for options in unselected patients and therapies that should only be offered in patients with distinct tumor profiles (e.g., BRAF mutations, KRAS G12C mutations, HER2 amplification, deficient MMR, or NTRK gene fusions). [ABSTRACT FROM AUTHOR]
Simple Summary: Malignant pleural mesothelioma is an invasive and drug-resistant tumor related to asbestos exposure, with limited therapy options. It is associated with an unfavorable prognosis and a 5-year survival rate of only 12%. Current standard-of-care treatment based on platinum-pemetrexed chemotherapy has been in place for the past two decades, though survival is increased by just a few months. In this article, we aim to review the current chemotherapy and immunotherapy options for this malignancy and highlight recent developments with regard to chemoimmunotherapy, targeted agents and cellular therapy. The incidence of malignant pleural mesothelioma is expected to increase globally. New treatment options for this malignancy are eagerly awaited to improve the survival and quality of life of patients. The present article highlights the results of recent advances in this field, analyzing data from several relevant trials. The heterogeneous tumor microenvironment and biology, together with the low mutational burden, pose a challenge for treating such tumors. So far, no single biomarker has been soundly correlated with targeted therapy development; thus, combination strategies are often required to improve outcomes. Locally applied vaccines, the expansion of genetically engineered immune cell populations such as T cells, the blockage of immune checkpoints that inhibit anti-tumorigenic responses and chemoimmunotherapy are among the most promising options expected to change the mesothelioma treatment landscape. [ABSTRACT FROM AUTHOR]
advanced thyroid cancer, targeted agents, adverse events, expert consensus, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract
Recently, targeted therapy has become the standard of care for advanced thyroid cancer. Although expert consensus on the management of adverse events in patients receiving targeted agents for radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) was formulated by Thyroid Cancer Committee of Chinese Society of Clinical Oncology in 2018, the tumor types which are eligible for targeted therapy have been extended to medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC), and targeted agents have been approved from multikinase inhibitors (MKIs) to BRAF inhibitors, MEK inhibitors, RET inhibitors and TRK inhibitors. Along with the widely used targeted agents with different mechanism, the management of adverse events for targeted agents needs to be standardized and improved, especially considering the specialties of the physicians who are involved in the targeted therapy for thyroid cancer are variable. Therefore, Thyroid Cancer Committee of Chinese Society of Clinical Oncology convened an expert task force charged with developing consensus to serves as a guidance to standardize utilization of targeted agents and to optimize clinical practice.
Breast cancer (BC) in elderly women is an increasing health issue due to demographic changes. BC tends to present later and may receive less than standard treatment options. More often, BC in elderly patients is endocrine-positive (HR+). The treatment of elderly patients with metastatic BC (mBC) represents a therapeutic challenge. In recent years, the treatment landscape of patients that are HR+/Her2-negative has changed due to the introduction in clinical practice of new targeted drugs, which have improved patient outcomes. Elderly patients are a small percentage of all patients enrolled in clinical trials and, to date, there are no standardized guidelines that define the best treatment option for this patient population. This can lead to undertreatment or overtreatment, impacting patient morbidity and mortality. Geriatric Assessment tools to tailor the treatment in elderly patients are underused because they are long and difficult to apply in a busy routine clinical practice. For all these reasons, there is an urgent need to produce data about the best treatment for elderly patients with HR+ mBC. Herein, we report data from randomized clinical trials and real-world evidence on the therapeutic options for HR+ Her2-negative mBC elderly patients and explore future treatment directions. [ABSTRACT FROM AUTHOR]
Ruiyang Xie, Jie Wu, Bingqing Shang, Xingang Bi, Weixing Jiang, Chuanzhen Cao, Aiping Zhou, Hongzhe Shi, and Jianzhong Shou
Subjects
mTOR inhibitor, renal cell carcinoma, targeted agents, VEGF‐TKI, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract
Abstract Objective For patients with advanced or metastatic renal cell carcinoma (RCC), the dose of targeted agents was recommended in combination with immune checkpoint inhibitors. We performed a network meta‐analysis to describe a categorized safety ranking profile and assess the adaptability of the combination options of targeted agents. Methods The targeted agents refer to vascular endothelial growth factor tyrosine kinase inhibitors (VEGF‐TKIs) and mammalian target of rapamycin (mTOR) inhibitors. Randomized controlled trials comparing these drugs were enrolled in a Bayesian model network meta‐analysis. Results Nineteen clinical trials with 11 treatments and 10,615 patients were included. For grade ≥ 3 adverse events (AEs), compared with placebo, lenvatinib plus everolimus showed worse safety than all other treatments except for lenvatinib (placebo vs. OR 0.23, 95% CI 0.07–0.78). Everolimus was generally the safest agent (OR 1.23, 95% CI 0.50–3.14). Sorafenib arose the least renal AEs (placebo vs. OR 0.85, 95% CI 0.06–11.64), whereas lenvatinib plus everolimus had the highest risk of renal toxicity (placebo vs. 0.17 95% CI 0.01–1.02). For gastrointestinal symptoms, everolimus was related to much lower toxicity than other agents. In the respiratory safety analysis, tivozanib (placebo vs. OR 0.15, 95% CI 0.07–0.31) and axitinib (OR 5.43, 95% CI 3.26–9.22) were the riskiest agents. In terms of hepatobiliary (placebo vs. OR 0.44, 95% CI 0.09–2.10) and hemotoxicity (placebo vs. OR 1.03, 95% CI 0.14–7.68) related AEs, lenvatinib was found to be the safest treatment compared to placebo. Conclusions Everolimus, with the best safety of grade ≥ 3, gastrointestinal, and respiratory AEs, was more likely to be considered for combination therapies. Lenvatinib appears to be the safest for blood/lymphatic and hepatobiliary AEs. For patients with renal disorders, sorafenib arises the least renal toxicity AEs. This study will guide treatment options and optimize the trial design for advanced or metastatic RCC.
Xin Zhao,1 Chenhao Zhang,2 Yi An,3 Zixuan Zhang,3 Jiahe Zhao,3 Xinwen Zhang,3 Yue Yang,4 Wei Cao4 1Department of Rheumatology, Guang’anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China; 2Department of Emergency, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing, 100102, People’s Republic of China; 3Department of School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 4Department of Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing, 100102, People’s Republic of ChinaCorrespondence: Wei Cao, Department of Wangjing Hospital of China Academy of Chinese Medical Sciences, No. 6 Zhonghuan South Road, Chaoyang District, Beijing, 100102, People’s Republic of China, Tel +86 10-84739099, Email caoweicw0@126.comAbstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by polyarticular, symmetric, and aggressive inflammation of the small joints in the hands and feet, resulting in dysfunction. With progress and development in medicine, treatment of RA is constantly evolving, making several drugs available for the treatment of RA. From the nonsteroidal anti-inflammatory drugs (NSAIDs) at the start of illness to glucocorticoids and then to conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs), therapeutic-use drugs for RA have been keeping pace with scientific research. However, various types of drugs have additional side effects when used over the long-term. New and emerging biological and targeted agents have been widely applied in recent years; however, the side effects have not been thoroughly investigated. In this paper, we review the research progress on liver damage caused by novel biological and targeted agents available for RA treatment. The aim is to provide a reference for rational clinical administration of such drugs.Keywords: liver damage, novel biological agents, research progress, rheumatoid arthritis, targeted agents
Paul, Megan R, Pehlivan, Katherine C, Milburn, Mehrzad, Yeh-Nayre, Lanipua, Elster, Jennifer, and Crawford, John R
Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Infectious Diseases, Pediatric, Brain Disorders, Brain Cancer, Neurosciences, Clinical Trials and Supportive Activities, Rare Diseases, Clinical Research, Biotechnology, Cancer, Adolescent, Antineoplastic Agents, Central Nervous System Neoplasms, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Infant, Male, Prognosis, Pyridones, Pyrimidinones, Retrospective Studies, brain tumors, trametinib, targeted agents, MEK, Cardiorespiratory Medicine and Haematology, Oncology & Carcinogenesis, Cardiovascular medicine and haematology
Abstract
MEK inhibitors are an emerging therapy with increasing use in mitogen-activated protein kinase-driven central nervous system (CNS) tumors. There is limited data regarding efficacy and toxicity in pediatric patients. We report our clinical experience with trametinib-based therapy for the treatment of 14 consecutive pediatric patients with recurrent low-grade glioma (N=11) or high-grade CNS tumors (N=3) with MAP kinase pathway mutations. Patients received trametinib as monotherapy (N=9) or in combination (N=5) with another antineoplastic agent. Nine patients (64%) were progression free during treatment. Five patients showed a partial response, while 4 had stable disease. Two patients (14%) progressed on therapy. All partial responses were in patients with low-grade tumors. The remaining 3 patients were not evaluable due to toxicity limiting duration of therapy. Two of 3 patients with low-grade glioma with leptomeningeal dissemination showed radiographic treatment response. Five patients reported improved clinical symptoms while on trametinib. Adverse events on trametinib-based therapy included dermatologic, mouth sores, fever, gastrointestinal, infection, neutropenia, headache, and fatigue, and were more common in patients using combination therapy. Trametinib-based therapy demonstrated signals of efficacy in our single institutional cohort of pediatric patients with mitogen-activated protein kinase-driven CNS tumors. Our observations need to be confirmed in a clinical trial setting.
Purpose: The National Institutes of Health's policy for the inclusion of females in clinical research was a pivotal step towards the consideration of sex as a biological variable, which is of particular importance in oncology, given differential incidence and outcomes of cancer between the sexes, and known pharmacodynamic, pharmacokinetic, and immunological differences. Therefore, we aim to investigate if such biological sex-based differences translate to clinically meaningful outcome differences from recently approved systemic oncology therapies. Methods: A systematic review of randomized control trials (RCTs) cited in Food and Drug Administration, European Medicines Agency, and Health Canada approvals was conducted. Chemotherapy, targeted agents, and immunotherapy RCTs reporting sex-based sub-group analyses for overall/progression-free survival (OS/PFS) were considered. Hazard ratios (HRs) and 95% confidence intervals (CIs) were utilized. Sensitivity analyses for survival endpoints, drug type, and cancer site were conducted. Results: Ninety-nine RCTs were included, representing 62,384 patients (23,574 (38%) female). Pooled OS HRs [95% CIs] were 0.77 [0.72–0.81] and 0.76 [0.72–0.79] for females and males, respectively (P = 0.73), and 0.51 [0.47–0.56] and 0.57 [0.53–0.61] (P = 0.08) for PFS. Sensitivity analyses yielded similar results. No RCTs reported sex-based toxicity or quality-of-life (QOL) data. Conclusion: Female and male patients appear to derive comparable benefits from recently approved systemic oncology therapies. Future RCTs are encouraged to report sex-based toxicity and QOL data. [ABSTRACT FROM AUTHOR]
Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular syndrome characterized by a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, which eventually leads to right heart failure and even death. Although the exact mechanism of PAH is not fully understood, pulmonary vasoconstriction, vascular remodeling, immune and inflammatory responses, and thrombosis are thought to be involved in the development and progression of PAH. In the era of non-targeted agents, PAH had a very dismal prognosis with a median survival time of only 2.8 years. With the deep understanding of the pathophysiological mechanism of PAH as well as advances in drug research, PAH-specific therapeutic drugs have developed rapidly in the past 30 years, but they primarily focus on the three classical signaling pathways, namely the endothelin pathway, nitric oxide pathway, and prostacyclin pathway. These drugs dramatically improved pulmonary hemodynamics, cardiac function, exercise tolerance, quality of life, and prognosis in PAH patients, but could only reduce pulmonary arterial pressure and right ventricular afterload to a limited extent. Current targeted agents delay the progression of PAH but cannot fundamentally reverse pulmonary vascular remodeling. Through unremitting efforts, new therapeutic drugs such as sotatercept have emerged, injecting new vitality into this field. This review comprehensively summarizes the general treatments for PAH, including inotropes and vasopressors, diuretics, anticoagulants, general vasodilators, and anemia management. Additionally, this review elaborates the pharmacological properties and recent research progress of twelve specific drugs targeting three classical signaling pathways, as well as dual-, sequential triple-, and initial triple-therapy strategies based on the aforementioned targeted agents. More crucially, the search for novel therapeutic targets for PAH has never stopped, with great progress in recent years, and this review outlines the potential PAH therapeutic agents currently in the exploratory stage to provide new directions for the treatment of PAH and improve the long-term prognosis of PAH patients. [ABSTRACT FROM AUTHOR]
Scherm, Angelika, Ippen, Franziska Maria, Hau, Peter, Baurecht, Hansjörg, Wick, Wolfgang, Gempt, Jens, Knüttel, Helge, Leitzmann, Michael F., and Seliger, Corinna
Subjects
BRAIN tumors, CLINICAL trials, GLIOBLASTOMA multiforme, PROTEIN kinase inhibitors, HISTONE deacetylase inhibitors, ELECTRIC field therapy
Abstract
Glioblastoma (GB) is the most common malignant primary brain tumor in adults. The standard of care for newly diagnosed GB involves surgical resection followed by radiochemotherapy with temozolomide, with or without tumor‐treating fields. In recent years, various efforts have been made to identify suitable molecularly targeted treatment options for malignant brain tumors. This meta‐analysis provides an overview of recently published randomized controlled trials (RCTs) with and without molecular stratification, analyzing targeted agents in patients with newly diagnosed GB. The Cochrane Library, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform, and Google Scholar were searched for RCTs on targeted therapies in patients with newly diagnosed glioblastoma. Hazard ratios (HRs) for overall survival (OS) and progression‐free survival (PFS) were extracted and pooled in a random‐effects meta‐analysis. Twelve RCTs (n = 3941 patients) involving protein kinase inhibitors, proteasome and histone deacetylase inhibitors, anti‐angiogenic approaches and poly (ADP‐ribose) polymerase (PARP) inhibitors were included in the meta‐analysis. None of the targeted agents achieved a significant benefit with regard to OS (HR = 0.98 [95% confidence interval (CI) 0.86‐1.11, P =.7731]). By comparison, targeted therapy showed a benefit for PFS (HR = 0.83 [95% CI 0.74‐0.94, P =.0037]), especially for patients with an unmethylated O6‐methylguanine‐DNA‐methyltransferase (MGMT) promoter (0.75 [95% CI 0.56‐0.99, P =.0440]). Prolongation of PFS was largely driven by VEGF inhibition with bevacizumab (HR = 0.70 [95% CI 0.61‐0.80, P =.0000]). VEGF inhibition with bevacizumab prolonged PFS in patients with newly diagnosed glioblastoma compared to standard care. However, no improvement in OS was observed with any of the targeted agents. [ABSTRACT FROM AUTHOR]
Oberoi, Sapna, Choy, Edwin, Chen, Yen-Lin, Scharschmidt, Thomas, and Weiss, Aaron R.
Abstract
Opinion statement: Extremity soft tissue sarcoma (ESTS) constitutes the majority of patients with soft tissue sarcoma (STS). Patients with localized high-grade ESTS > 5 cm in size carry a substantial risk of developing distant metastasis on follow-up. A neoadjuvant chemoradiotherapy approach can enhance local control by facilitating resection of the large and deep locally advanced tumors while trying to address distant spread by treating the micrometastasis for these high-risk ESTS. Preoperative chemoradiotherapy and adjuvant chemotherapy are often used for children with intermediate- or high-risk non-rhabdomyosarcoma soft tissue tumors in North America and Europe. In adults, the cumulative evidence supporting preoperative chemoradiotherapy or adjuvant chemotherapy remains controversial. However, some studies support a possible benefit of 10% in overall survival (OS) for high-risk localized ESTS, especially for those with a probability of 10-year OS < 60% using validated nomograms. Opponents of neoadjuvant chemotherapy argue that it delays curative surgery, compromises local control, and increases the rate of wound complications and treatment-related mortality; however, the published trials do not support these arguments. Most treatment-related side effects can be managed with adequate supportive care. A coordinated multidisciplinary approach involving sarcoma expertise in surgery, radiation, and chemotherapy is required to achieve better outcomes for ESTS. The next generation of clinical trials will shed light on how comprehensive molecular characterization, targeted agents and/or immunotherapy can be integrated into the upfront trimodality treatment to improve outcomes. To that end, every effort should be made to enroll these patients on clinical trials, when available. [ABSTRACT FROM AUTHOR]
Objective: For patients with advanced or metastatic renal cell carcinoma (RCC), the dose of targeted agents was recommended in combination with immune checkpoint inhibitors. We performed a network meta‐analysis to describe a categorized safety ranking profile and assess the adaptability of the combination options of targeted agents. Methods: The targeted agents refer to vascular endothelial growth factor tyrosine kinase inhibitors (VEGF‐TKIs) and mammalian target of rapamycin (mTOR) inhibitors. Randomized controlled trials comparing these drugs were enrolled in a Bayesian model network meta‐analysis. Results: Nineteen clinical trials with 11 treatments and 10,615 patients were included. For grade ≥ 3 adverse events (AEs), compared with placebo, lenvatinib plus everolimus showed worse safety than all other treatments except for lenvatinib (placebo vs. OR 0.23, 95% CI 0.07–0.78). Everolimus was generally the safest agent (OR 1.23, 95% CI 0.50–3.14). Sorafenib arose the least renal AEs (placebo vs. OR 0.85, 95% CI 0.06–11.64), whereas lenvatinib plus everolimus had the highest risk of renal toxicity (placebo vs. 0.17 95% CI 0.01–1.02). For gastrointestinal symptoms, everolimus was related to much lower toxicity than other agents. In the respiratory safety analysis, tivozanib (placebo vs. OR 0.15, 95% CI 0.07–0.31) and axitinib (OR 5.43, 95% CI 3.26–9.22) were the riskiest agents. In terms of hepatobiliary (placebo vs. OR 0.44, 95% CI 0.09–2.10) and hemotoxicity (placebo vs. OR 1.03, 95% CI 0.14–7.68) related AEs, lenvatinib was found to be the safest treatment compared to placebo. Conclusions: Everolimus, with the best safety of grade ≥ 3, gastrointestinal, and respiratory AEs, was more likely to be considered for combination therapies. Lenvatinib appears to be the safest for blood/lymphatic and hepatobiliary AEs. For patients with renal disorders, sorafenib arises the least renal toxicity AEs. This study will guide treatment options and optimize the trial design for advanced or metastatic RCC. [ABSTRACT FROM AUTHOR]
Esteban-Villarrubia, Jorge, Torres-Jiménez, Javier, Bueno-Bravo, Carolina, García-Mondaray, Rebeca, Subiela, José Daniel, and Gajate, Pablo
Subjects
*THERAPEUTIC use of antineoplastic agents, *PERIOPERATIVE care, *ADJUVANT chemotherapy, *CYSTECTOMY, *IMMUNE checkpoint inhibitors, *CANCER invasiveness, *CANCER relapse, *METASTASIS, *COMBINED modality therapy, *IMMUNOTHERAPY, BLADDER tumors
Abstract
Simple Summary: The risk of recurrence of patients with localized muscle-invasive bladder carcinoma (MIBC) is still high. The outcomes of surgery and perioperative therapy are limited, and several patients are not candidates for neoadjuvant chemotherapy and have no further alternatives available. In recent years, many drugs have been evaluated in the metastatic setting. This review summarizes the evidence of perioperative treatment with these new drugs for MIBC, emphasizing immunotherapy and targeted agents. Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy is the current standard of care for muscle-invasive bladder cancer (MIBC). However, less than half of patients are candidates for this treatment, and 50% will develop metastatic disease. Adjuvant chemotherapy could be offered if neoadjuvant treatment has not been administered for suitable patients. It is important to reduce the risk of systemic recurrence and improve the prognosis of localized MIBC. Systemic therapy for metastatic urothelial carcinoma has evolved in recent years. Immune checkpoint inhibitors and targeted agents, such as antibody-drug conjugates or FGFR inhibitors, are new therapeutic alternatives and have shown their benefit in advanced disease. Currently, several clinical trials are investigating the role of these drugs, as monotherapy and in combination with chemotherapy, in the neoadjuvant and adjuvant settings with promising outcomes. In addition, the development of predictive biomarkers could predict responses to neoadjuvant therapies. [ABSTRACT FROM AUTHOR]
Keywords: chemo-immunotherapy; chronic lymphocytic leukemia; targeted agents EN chemo-immunotherapy chronic lymphocytic leukemia targeted agents 201 204 4 02/03/23 20230201 NES 230201 PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1002/hon.3047. 1 TABLE Management of chronic lymphocytic leukemia (CLL) patients: Staging, criteria for starting treatment, response assessment and follow up HT
2020 (before first line)
2021 (before second line)
N = 35 (%)
N = 42 (%)
(1) What do you perform before starting first/second-line therapy? Dear Editor, different clinical trials on Chronic Lymphocytic Leukemia (CLL) indicate the superiority of targeted agents (TA), as ibrutinib, acalabrutinib and venetoclax, respect to chemo-immunotherapy (CIT). [Extracted from the article]
Ahmad KH Ibrahimi, Maysa Al-Hussaini, Dima Abu Laban, Rula Ammarin, Lina Wehbeh, and Abdelatif Al-Mousa
Subjects
brain metastasis, cetuximab, colorectal cancer, targeted agents, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract
Brain metastasis (BM) from colorectal cancer (CRC) is rare and associated with poor prognosis. The mainstay of treatment for BM from CRC is radiotherapy, systemic treatment options for CRC can include novel targeted agents, conventional chemotherapy or a combination of both. Nevertheless, the efficacy of these systemic treatment options against BM from CRC is not yet fully established. Cetuximab, a monoclonal antibody, has been shown to be effective in patients with KRAS wild-type metastatic CRC. The combination of cetuximab with oxaliplatin-based chemotherapy is commonly utilized as a systemic treatment for metastatic CRC. Hereby, we report a case of BM from CRC with significant response after capecitabine and oxaliplatin (XELOX) combined with cetuximab.
Langerhans cell histiocytosis(LCH)and Langerhans cell sarcoma(LCS)are characterized by clone proliferation of Langerhans-type cells, which may occur concurrently or sequentially with T-cell acute lymphoblastic leukemia (T-ALL) and other Lymphoid neoplasms. A 15-year old female patient diagnosed with T-ALL developed LCH involving multiple systems during maintenance chemotherapy of T-AL. After treated with chemotherapy with improved result, the patient showed progression of the illness and refractory to the second-line treatment. We found c.G35A (p.G12D)mutation in the KRAS gene and used the targeted drug Trametinib for treatment. The treatment proved effective, leading to partial remission within a week. Three months after Trametinib treatment, the patient developed new lymphadenopathy. Biopsy revealed the existence of LCS. The disease progressed quickly, and the patient died 7 days after diagnosis of LCS. The case of patients with T-ALL then developing LCH and LCS sequentially is extraordinarily rare. The causes of the case is unclear and may be related to cell transdifferentiation, clonal evolution, and chemotherapy. Targeted drugs can contain this disease for a short time.
Bewersdorf, Jan Philipp, Shallis, Rory M., Derkach, Andriy, Goldberg, Aaron D., Stein, Anthony, Stein, Eytan M., Marcucci, Guido, Zeidan, Amer M., Shimony, Shai, DeAngelo, Daniel J., Stone, Richard M., Aldoss, Ibrahim, Ball, Brian J., and Stahl, Maximilian
FLT3, IDH1 and IDH2 inhibitors as well as venetoclax in combination with hypomethylating agents or low-dose cytarabine have expanded treatment options for patients with acute myeloid leukemia (AML). However, little data exist on the efficacy of venetoclax-based therapies in AML patients previously treated with FLT3 or IDH1/2 inhibitors. In this multicenter, retrospective cohort study, we included 44 patients who received venetoclax-based therapy after FLT3, IDH1 or IDH2 inhibitors. The overall response rate (ORR; composite of complete remission [CR]/CR with incomplete count recovery, partial remission, and morphologic leukemia free state) was 56.8% (18.2% CR) and a median overall survival of 9.2 months. While 6 out of 7 patients with IDH1 mutations who had previously been treated with ivosidenib responded to venetoclax-based therapy, FLT3-ITD mutations were associated with a lower response rate. Our data suggest that venetoclax can be an effective salvage therapy in patients previously treated with IDH1/2 or FLT3 inhibitors. [ABSTRACT FROM AUTHOR]
Second-line treatments are standard care for advanced hepatocellular carcinoma (HCC) patients with preserved liver function who are intolerant of or progress on first-line therapy. However, determinants of treatment benefit and post-treatment survival (PTS) remain unknown. HCC patients previously treated with sorafenib and enrolled in second-line clinical trials were pooled according to the investigational treatment received and the subsequent regulatory approval: approved targeted agents and immune checkpoint inhibitors (AT) or other agents (OT) not subsequently approved. Univariate and multivariate analyses using Cox proportional hazards models established relationships among treatments received, clinical variables, and overall survival (OS) or PTS. For 174 patients (80 AT; 94 OT) analyzed, baseline factors for longer OS in multivariate analysis were second-line AT, absence of both portal vein thrombosis and extrahepatic spread (EHS). Treatment with AT (versus OT) was associated with significantly longer OS among patients with EHS (pinteraction = 0.005) and patients with low neutrophil-to-lymphocyte ratio (NLR; pinteraction = 0.032). Median PTS was 4.0 months (95% CI 2.8–5.3). At second-line treatment discontinuation, alpha-fetoprotein (AFP) levels <400 ng/dl, albumin-bilirubin (ALBI) grade 1, and enrolment onto subsequent trials independently predicted longer PTS. Treatment with AT, PVT, and EHS were prognostic factors for OS, while AFP, ALBI grade and enrolment onto a third-line trial were prognostic for PTS. Presence of EHS and low NLR were predictors of greater OS benefit from AT. [ABSTRACT FROM AUTHOR]
*CHRONIC lymphocytic leukemia, *SOMATIC mutation, *PROGNOSIS, *INCURABLE diseases, *AGAMMAGLOBULINEMIA, WESTERN countries
Abstract
With its heterogeneous biological features and clinical course, chronic lymphocytic leukemia (CLL), the most frequent adult leukemia in the Western world, is a paradigmatic condition requiring a tailored approach and a precise knowledge of the biology behind each individual patient. This personalized management is becoming even more crucial, since, after decades of preclinical work unravelling the key role of the B-cell receptor (BcR) signalling pathways and the anti-apoptotic mechanisms in CLL cell survival and proliferation, we have now BcR and BCL2 inhibitors available in clinical practice. Thanks to this, we are now able to exploit specific biomarkers to tailor our treatment strategies and improve long-term disease control, patient outcome and quality of life. That notwithstanding, as the disease itself remains incurable, novel challenges and unmet clinical needs have risen from the introduction of novel targeted agents, including mechanisms of resistance at both genetic and epigenetic levels. In this review, we summarize the currently established predictive biomarkers (i.e. IGHV mutation status and TP53 gene disruption) that should be applied in clinical practice to inform treatment decision in 2021 but also discuss the most promising prognostic biomarkers (B-cell receptor stereotypy, complex karyotype, somatic gene mutations, measurable residual disease - MRD) that might become key to define the management of our patients in a near future. [ABSTRACT FROM AUTHOR]
Natalja Eigeliene, Jatta Saarenheimo, Viktor Wichmann, Pia Österlund, and Antti Jekunen
Subjects
chemotherapy, liver resection, metastatic colorectal cancer, radiotherapy, targeted agents, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract
In the era of personalized medicine, systemic treatment with chemotherapy in combination with targeted drugs, tailored according to RAS and BRAF status, has improved the survival of patients with metastatic colorectal cancer (mCRC), but curative resection of metastases provides the only chance of cure. Here, we present a 40-year-old male with rectal adenocarcinoma and multiple bilateral synchronous liver metastases who has achieved long-term remission with multimodal treatment without resection of all metastatic lesions. This case emphasizes the need of repeated multidisciplinary team assessments and change of treatment intent if extraordinary responses are seen. The initial therapy consisted of short-course radiotherapy and surgery of the primary tumor followed by oxaliplatin-based combination chemotherapy and panitumumab with disease control intent. A complete radiologic response in >20 liver metastases in segments II–VIII was obtained. A biopsy-verified relapse of 3 liver metastases occurred at 9 months of treatment pause. Subsequently, major liver resection of 8 lesions was performed (4 with adenocarcinoma and 4 with cicatrix showing the challenge of disappearing lesions), followed by 6 months of adjuvant-like therapy. No relapse in MRI, PET, or CT has been noted since liver resection 6 years ago. Comprehensive genomic profiling of the primary tumor and liver metastases had similar driver mutations representing a low level of gene alteration and low diversity, possibly explaining the exceptional treatment response.
pulmonary arterial hypertension, medical management, endothelin pathway, nitric oxide pathway, prostacyclin pathway, targeted agents, Pharmacy and materia medica, RS1-441
Abstract
Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular syndrome characterized by a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, which eventually leads to right heart failure and even death. Although the exact mechanism of PAH is not fully understood, pulmonary vasoconstriction, vascular remodeling, immune and inflammatory responses, and thrombosis are thought to be involved in the development and progression of PAH. In the era of non-targeted agents, PAH had a very dismal prognosis with a median survival time of only 2.8 years. With the deep understanding of the pathophysiological mechanism of PAH as well as advances in drug research, PAH-specific therapeutic drugs have developed rapidly in the past 30 years, but they primarily focus on the three classical signaling pathways, namely the endothelin pathway, nitric oxide pathway, and prostacyclin pathway. These drugs dramatically improved pulmonary hemodynamics, cardiac function, exercise tolerance, quality of life, and prognosis in PAH patients, but could only reduce pulmonary arterial pressure and right ventricular afterload to a limited extent. Current targeted agents delay the progression of PAH but cannot fundamentally reverse pulmonary vascular remodeling. Through unremitting efforts, new therapeutic drugs such as sotatercept have emerged, injecting new vitality into this field. This review comprehensively summarizes the general treatments for PAH, including inotropes and vasopressors, diuretics, anticoagulants, general vasodilators, and anemia management. Additionally, this review elaborates the pharmacological properties and recent research progress of twelve specific drugs targeting three classical signaling pathways, as well as dual-, sequential triple-, and initial triple-therapy strategies based on the aforementioned targeted agents. More crucially, the search for novel therapeutic targets for PAH has never stopped, with great progress in recent years, and this review outlines the potential PAH therapeutic agents currently in the exploratory stage to provide new directions for the treatment of PAH and improve the long-term prognosis of PAH patients.
Lambertini, Matteo, Marrocco, Camilla, Spinaci, Stefano, Demeestere, Isabelle, and Anderson, Richard A.
Subjects
*AMENORRHEA, *IMMUNOTHERAPY, *DRUG side effects, *HORMONE receptor positive breast cancer, *HER2 positive breast cancer, *TRIPLE-negative breast cancer, *IMMUNE checkpoint inhibitors
Abstract
Two other analyses have reported on post-treatment amenorrhoea rates in premenopausal women receiving anti-HER2 therapies without prior exposure to anthracycline- and cyclophosphamide-based chemotherapy. Keywords: breast cancer; immunotherapy; oncofertility; targeted agents EN breast cancer immunotherapy oncofertility targeted agents 1 4 4 06/16/22 20220701 NES 220701 In recent years, survivorship has become an area of crucial importance in the care of cancer patients. In addition, T-DM1 is now approved as post-neoadjuvant treatment in patients with HER2-positive breast cancer without pathological complete response following chemotherapy and trastuzumab-based anti-HER2 therapy, and several newer antibody drug conjugates alone or in combination with other targeted agents are currently being investigated in the early setting. Adjuvant anti-HER2 therapy, treatment-related amenorrhea, and survival in premenopausal HER2-positive early breast cancer patients. [Extracted from the article]
Simple Summary: In this paper we perform an introduction about pregnancy-associated cancer (PAC) and transplacental passage of antineoplastic agents. Furthermore, we describe therapeutic use and potential toxic effects of chemotherapeutic drug (alkylating agents, antimetabolites agents, anthracyclines, topoisomerase inhibitors, antimitotic agents, actinomycin-D, bleomycin) and targeted agents during pregnancy. This manuscript may be a useful and practical guide for the management of PAC, which is a challenge for clinicians that have to consider alike maternal benefits and fetal potential risks correlated to the antineoplastic treatment. The incidence of PAC is relatively infrequent among pregnant women. However, it has gradually increased in recent years, becoming a challenging area for clinicians that should take into account in the same way maternal benefits and fetal potential risks correlated to the antineoplastic treatment. None of the antineoplastic drugs is completely risk-free during the pregnancy, the timing of exposure and transplacental transfer properties influence the toxicity of the fetus. Despite the lack of guidelines about the management of PAC, several studies have described the use and the potential fetal and neonatal adverse events of antineoplastic drugs during pregnancy. We provide a review of the available literature about the transplacental passage and fetal effects of chemotherapy and targeted agents, to guide the clinicians in the most appropriate choices for the management of PAC. [ABSTRACT FROM AUTHOR]
Simple Summary: Tumor cells are highly resistant to oxidative stress, but beyond a certain threshold, it may lead to apoptosis/necrosis. Thus, induced loss of redox balance can be a strategy used in anticancer therapies. However, the effectiveness of drugs contrasts with unknown mechanisms involved in the loss of fertility. Considering that cancer patients' life expectancy is increasing, it raises concerns about the unknown adverse effects. Therefore, new strategies should be pursued alongside explaining to the patients their options regarding the reproduction side effects. Tumor cells are highly resistant to oxidative stress resulting from the imbalance between high reactive oxygen species (ROS) production and insufficient antioxidant defenses. However, when intracellular levels of ROS rise beyond a certain threshold, largely above cancer cells' capacity to reduce it, they may ultimately lead to apoptosis or necrosis. This is, in fact, one of the molecular mechanisms of anticancer drugs, as most chemotherapeutic treatments alter redox homeostasis by further elevation of intracellular ROS levels or inhibition of antioxidant pathways. In traditional chemotherapy, it is widely accepted that most therapeutic effects are due to ROS-mediated cell damage, but in targeted therapies, ROS-mediated effects are mostly unknown and data are still emerging. The increasing effectiveness of anticancer treatments has raised new challenges, especially in the field of reproduction. With cancer patients' life expectancy increasing, many aiming to become parents will be confronted with the adverse effects of treatments. Consequently, concerns about the impact of anticancer therapies on reproductive capacity are of particular interest. In this review, we begin with a short introduction on anticancer therapies, then address ROS physiological/pathophysiological roles in both male and female reproductive systems, and finish with ROS-mediated adverse effects of anticancer treatments in reproduction. [ABSTRACT FROM AUTHOR]
HORMONE receptor positive breast cancer, ESTROGEN receptors, HORMONE therapy
Abstract
Estrogen receptor (ER+) breast cancer is the most frequently diagnosed breast cancer subtype. Currently, adjuvant treatment for early stage disease consists of endocrine therapy, with or without chemotherapy and bone-targeted therapy, delivered in a risk-adapted manner. Despite this multimodal approach, a significant proportion of high risk patients will develop incurable distant recurrences. There is an ongoing need to develop new treatment strategies that address the biologic causes of treatment failure and to identify the individual patients who can benefit from such interventions. Here we review the clinical investigation of targeted and novel therapies, including inhibitors of the PI3K-AKT-mTOR pathway, oral selective estrogen receptor degraders (SERDs), and PARP-inhibitors for the treatment of early ER+ breast cancer. Furthermore, we highlight opportunities in biomarker development to help guide the delivery of escalated adjuvant strategies. [ABSTRACT FROM AUTHOR]
George D. Wilson, Thomas G. Wilson, Alaa Hanna, Mohamad Dabjan, Katie Buelow, John Torma, Brian Marples, and Sandra Galoforo
Subjects
Head and neck cancer, Radiation, Targeted agents, Xenografts, Growth delay, Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract
Background and purpose: There has been little success targeting individual genes in combination with radiation in head and neck cancer. In this study we investigated whether targeting two key pathways simultaneously might be more effective. Materials and methods: We studied the effect of combining dacomitinib (pan-HER, irreversible inhibitor) and gedatolisib (dual PI3K/MTOR inhibitor) with radiation in well characterized, low passage xenograft models of HNSCC in vitro and in vivo. Results: Dacomitinib showed differential growth inhibition in vitro that correlated to EGFR expression whilst gedatolisib was effective in both cell lines. Neither agent radiosensitized the cell lines in vitro. In vivo studies demonstrated that dacomitinib was an effective agent alone and in combination with radiation whilst the addition of gedatolisib did not enhance the effect of these two modalities despite inhibiting phosphorylation of key genes in the PI3K/MTOR pathway. Conclusions: Our results showed that combining two drugs with radiation provided no added benefit compared to the single most active drug. Dacomitinib deserves more investigation as a radiation sensitizing agent in HNSCC.
Breast cancer, Adjuvant therapy, Endocrine therapy, Targeted agents, Estrogen receptor, mTOR, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract
Estrogen receptor (ER+) breast cancer is the most frequently diagnosed breast cancer subtype. Currently, adjuvant treatment for early stage disease consists of endocrine therapy, with or without chemotherapy and bone-targeted therapy, delivered in a risk-adapted manner. Despite this multimodal approach, a significant proportion of high risk patients will develop incurable distant recurrences. There is an ongoing need to develop new treatment strategies that address the biologic causes of treatment failure and to identify the individual patients who can benefit from such interventions. Here we review the clinical investigation of targeted and novel therapies, including inhibitors of the PI3K-AKT-mTOR pathway, oral selective estrogen receptor degraders (SERDs), and PARP-inhibitors for the treatment of early ER+ breast cancer. Furthermore, we highlight opportunities in biomarker development to help guide the delivery of escalated adjuvant strategies.
lung cancer, mortality, intensive care unit, chemotherapy, targeted agents, Medicine (General), R5-920
Abstract
PurposeWe investigated the intensive care unit (ICU) outcomes of patients who used targeted therapy compared to those who received cytotoxic chemotherapy.Materials and MethodsThis study was based on Korean administrative health insurance claims from 2015 to 2019. We extracted data on lung cancer patients (>18 years old) who were admitted to the ICU after receiving chemotherapy.Results6,930 lung cancer patients who received chemotherapy within 30 days before ICU admission were identified; the patients received cytotoxic chemotherapy (85.4%, n = 5,919) and molecular targeted therapy (14.5%, n = 1,011). Grade 4 neutropenia was identified only in the cytotoxic chemotherapy group (0.6%). Respiratory failure requiring ventilator treatment was more common in the cytotoxic chemotherapy group than in the targeted therapy group (HR, 3.30; 95% CI, 2.99–3.63), and renal failure requiring renal replacement therapy was not significantly different between the two groups (HR, 1.57; 95% CI, 1.36–1.80). Patients who received targeted chemotherapy stayed longer in the ICU than the cytotoxic chemotherapy. The 28-day mortality was 23.4% (HR, 0.79; 95% CI, 0.67–0.90, p < 0.05) among patients who received targeted agents compared with 29.6% among patients who received cytotoxic chemotherapy.ConclusionTargeted chemotherapy for lung cancer may contribute to increasing access to critical care for lung cancer patients, which may play a role in improving critical care outcomes of lung cancer patients.
Newer anticancer drugs have revolutionized cancer treatment in the last decade, but conventional chemotherapy still occupies a central position in many cancers, with combination therapy and newer methods of delivery increasing their efficacy while minimizing toxicities. We discuss the retinal toxicities of anticancer drugs with an emphasis on the mechanism of toxicity. Uveitis is seen with the use of v-raf murine sarcoma viral oncogene homolog B editing anticancer inhibitors as well as immunotherapy. Most of the cases are mild with only anterior uveitis, but severe cases of posterior uveitis, panuveitis, and Vogt-Koyanagi-Harada-like disease may also occur. In the retina, a transient neurosensory detachment is observed in almost all patients on mitogen-activated protein kinase kinase (MEK) inhibitors. Microvasculopathy is often seen with interferon α, but vascular occlusion is a more serious toxicity caused by interferon α and MEK inhibitors. Crystalline retinopathy with or without macular edema may occur with tamoxifen; however, even asymptomatic patients may develop cavitatory spaces seen on optical coherence tomography. A unique macular edema with angiographic silence is characteristic of taxanes. Delayed dark adaptation has been observed with fenretinide. Interestingly, this drug is finding potential application in Stargardt disease and age-related macular degeneration. [ABSTRACT FROM AUTHOR]
ESOPHAGEAL cancer, CANCER treatment, NIVOLUMAB, OVERALL survival, CHEMORADIOTHERAPY
Abstract
Background: Concurrent chemoradiotherapy (CRT) is the preferred treatment strategy for inoperable esophageal cancer (EC). However, the effect of CRT needs to be improved. Methods: This study comprehensively analyzed targeted agents combined with CRT for the treatment of EC by a network meta-analysis. The search was performed in public databases from incipient to 5 August 2021. Randomized controlled trials comparing the effect of targeted agents combined with CRT and CRT alone on EC patients were included. Results: Ten studies were included. For progression-free survival (PFS), nivolumab (67.4%) and erlotinib (64.6%) had advantages based on Cox analysis. Regarding the frequency of PFS, cetuximab (OR: 1.39; 95% CI: 1.01, 1.91; p=0.042) and nivolumab (OR: 1.81; 95% CI: 1.34, 2.44; p<0.01) were significantly superior to the control. For overall survival (OS), nivolumab (71.6%) in Cox analysis and nimotuzumab (69.7%) in frequency analysis were found to have relative advantages. Nimotuzumab combined with CRT was significantly better than the control with regard to endoscopic and the pathologic complete response (epCR; OR: 2.81; 95% CI: 1.28, 6.14; p=0.011) and objective response rate (ORR; 4.71; 95% CI: 1.45, 15.29; p=0.008). The targeted drugs were not associated with significant SEA risk. Conclusion: In conclusion, compared to CRT alone, cetuximab and nivolumab combined with CRT were found to significantly improve the PFS rate only based on the frequency results. However, there was no benefit in terms of OS. For epCR and ORR, nimotuzumab was better than the blank control. Considering the limitations in this study, more well-designed RCTs are needed in the future to validate the results. [ABSTRACT FROM AUTHOR]
Monteiro, Ana Raquel, Conde, Rita Saúde, Basto, Raquel, Sclafani, Francesco, Deleporte, Amélie, Hendlisz, Alain, and Dal Lago, Lissandra
Abstract
Targeted agents have been increasingly used in different malignancies and are associated with improved survival outcomes, including gastrointestinal cancers. Their use in the treatment of older patients is appealing given their favorable toxicity profile. In the last years, this subgroup of patients has been attracting increased interest given their representativeness and specific clinical needs. Nonetheless, the lack of data on efficacy and safety of standard treatments in older patients hinders proper evidence-based decision-making, leaving most therapeutic recommendations to be extrapolated from registration trials with low representation of older and frail patients. However, even if most decisions regarding the use of targeted agents in older patients with gastrointestinal cancer remain guided by subanalyses of large trials, data from recent older adult-specific trials are beginning to emerge, particularly in colorectal cancer. This review aims to summarize the existing evidence on treatment of older patients with gastrointestinal carcinomas (colon and rectum, stomach, esophagus, liver, and pancreas) with targeted agents (cetuximab, panitumumab, bevacizumab, ramucirumab, aflibercept, regorafenib, encorafenib, trastuzumab, sorafenib, lenvatinib, cabozantinib, erlotinib, olaparib), and place the evidence in a geriatric oncology perspective. [ABSTRACT FROM AUTHOR]
lung net, typical carcinoid, atypical carcinoid, everolimus, mammalian target of rapamycin (mtor) inhibitor, targeted agents, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract
Marta Peri,1 Nicola Fazio2 1Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy; 2Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, ItalyCorrespondence: Nicola Fazio via Ripamonti 435, Milan 20141, ItalyTel +390257489439Fax +390294379224Email nicola.fazio@ieo.itAbstract: Neuroendocrine tumors (NETs) of the lung are well-differentiated neuroendocrine neoplasms (NENs) with a heterogeneous clinical behaviour. Unlike gastroenteropancreatic NENs where therapeutic armamentarium clearly increased over the last decade, everolimus represented the only clinical practical innovation for lung NET patients over the last years. Therefore, for lung NETs, a multidisciplinary discussion within a dedicated team remains critical for an adequate decision-making. Although the main regulatory authorities considered the everolimus-related evidence is enough to approve the drug in advanced lung NETs, several clinical features deserve to be discussed. In this review, we systemically and critically analysed the main clinical studies including patients with advanced lung NETs receiving everolimus. Furthermore, we reported the biological and clinical background of everolimus in lung NET setting. The purpose of this review is to help clinical community to contextualize evidence and experience for a personalised use of this drug in clinical practice in the context of advanced lung NET patients.Keywords: lung NET, typical carcinoid, atypical carcinoid, everolimus, mammalian target of rapamycin (mTOR) inhibitor, targeted agents
Jing Qi, 1 Xiuzhi Guo, 1 Aihua Li 2 1Department of Respiration Medicine, Tai’an Central Hospital, Tai’an; 2Department of Respiration Medicine, Yankuang Group General Hospital, Jining, ChinaCorrespondence: Aihua LiDepartment of Respiration Medicine, Yankuang Group General Hospital, 560 Kuangjian East Road, Jining, Shandong 273500, ChinaTel +86 537 536 7018Fax +86 537 536 7017Email lahykjtzyy@sohu.comBackground: Several published meta-analyses have confirmed that single-agent maintenance therapy in advanced non-small-cell lung cancer (NSCLC) can prolong time to disease progression and potentially increase overall survival (OS) in comparison to placebo. However, whether doublet maintenance therapy can improve the survival of advanced NSCLC remains undetermined.Methods: We searched several databases for relevant trials. Prospective randomized controlled trials comparing doublet vs single-agent maintenance therapy in NSCLC patients were included for analysis. Outcomes of interest were OS, progression-free survival (PFS), and incidence of grade 3/4 toxicities.Results: A total of 1,950 advanced-NSCLC patients from six trials were included for analysis. Our results showed that doublet maintenance therapy in NSCLC patients significantly improved PFS (HR 0.74, 95% CI 0.59– 0.93; P=0.010), but not for OS (HR 0.95, 95% CI 0.85– 1.07; P=0.40) in comparison with single-agent maintenance therapy. Subgroup analysis by maintenance regimen showed that pemetrexed plus bevacizumab maintenance therapy significantly improved PFS, but not OS. In addition, there was no significant risk difference between doublet and single-agent maintenance therapy in terms of grade 3/4 hematologic and nonhematologic toxicities.Conclusion: Our study suggests that doublet maintenance therapy in advanced-NSCLC patients demonstrates PFS benefits, but not OS benefits, in comparison with single-agent maintenance therapy. Future trials are suggested to assess the long-term clinical benefit of doublet maintenance treatment in NSCLC patients and its impact on health-related quality of life.Keywords: targeted agents, maintenance therapy, doublet, single agent, meta-analysis
Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of tumours, which can be classified into neuroendocrine tumours (NETs), neuroendocrine carcinomas (NECs) and mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs). To date, there is no consensus regarding the optimal therapy, which usually depends on the primary location and classification, according to morphological features of differentiation and proliferation rates. Nevertheless, multidisciplinary strategies combining medical treatments and locoregional strategies have yielded better efficacy results. Here, we report the case of a patient diagnosed with a nonfunctional rectal NECs with metastatic widespread to pelvic lymph nodes and bilateral lung metastases. The patient received three cycles of platinumetoposide, concomitantly with palliative radiotherapy. Although CT scan after three cycles showed a significant partial response, there was an early fatal progression only 3 months after having stopped systemic therapy. As formerly described in the literature, this case highlights the aggressive behaviour of NECs, rare tumours that often present in advanced stages at diagnosis. Lately, new insights into the molecular biology of NECs have unveiled the possibility of using novel drugs, such as targeted agents or immunotherapy, in molecularly selected subgroups of patients. In this review, we discuss the current management of this rare entity and provide an overview of the most relevant molecular findings, whilst illustrating the potential value that prescreening panels can offer, searching for actionable targets (MSI/dMMR, PD-L1, BRAFv600E) to guide therapy with promising agents that could fill a void in this disease.